ABCA4 突变是孟德尔视网膜疾病的最常见原因。该基因的临床评估具有挑战性，因为其极端的等位基因多样性、大部分非外显子突变以及广泛的相关疾病。我们使用患者来源的视网膜类器官以及来自一大群 ABCA4 相关视网膜疾病患者的 DNA 样本和临床数据来研究 ABCA4 变异 (IVS30  1321 A > G) 的致病性，该变异在 2% 的患者中杂合发生。欧洲人。我们发现这种变异会导致感光细胞中的基因错误剪接，从而导致生成的蛋白质包含 36 个不正确的氨基酸，然后过早停止。我们还调查了 10 名含有该突变的复合基因型患者的表型。他们首次视力丧失的中位年龄为 39 岁，属于 ABCA4 疾病患者中病情最轻的五分之一。我们得出的结论是，IVS30  1321 A > G 变体在足够宽松的遗传背景下与足够有害的相反等位基因配对时会导致疾病。© 作者 2023。由牛津大学出版社出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Mutations in ABCA4 are the most common cause of Mendelian retinal disease. Clinical evaluation of this gene is challenging because of its extreme allelic diversity, the large fraction of non-exomic mutations, and the wide range of associated disease. We used patient-derived retinal organoids as well as DNA samples and clinical data from a large cohort of patients with ABCA4-associated retinal disease to investigate the pathogenicity of a variant in ABCA4 (IVS30 + 1321 A > G) that occurs heterozygously in 2% of Europeans. We found that this variant causes mis-splicing of the gene in photoreceptor cells such that the resulting protein contains 36 incorrect amino acids followed by a premature stop. We also investigated the phenotype of 10 patients with compound genotypes that included this mutation. Their median age of first vision loss was 39 years, which is in the mildest quintile of a large cohort of patients with ABCA4 disease. We conclude that the IVS30 + 1321 A > G variant can cause disease when paired with a sufficiently deleterious opposing allele in a sufficiently permissive genetic background.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.